Synthesis of Cyclic Fragrances via Transformations of Alkenes, Alkynes and Enynes: Strategies and Recent Progress

Abstract

With increasing demand for customized commodities and the greater insight and understanding of olfaction, the synthesis of fragrances with diverse structures and odor characters has become a core task. Recent progress in organic synthesis and catalysis enables the rapid construction of carbocycles and heterocycles from readily available unsaturated molecular building blocks, with increased selectivity, atom economy, sustainability and product diversity. In this review, synthetic methods for creating cyclic fragrances, including both natural and synthetic ones, will be discussed, with a focus on the key transformations of alkenes, alkynes, dienes and enynes. Several strategies will be discussed, including cycloaddition, catalytic cyclization, ring-closing metathesis, intramolecular addition, and rearrangement reactions. Representative examples and the featured olfactory investigations will be highlighted, along with some perspectives on future developments in this area.

Keywords: asymmetric organocatalysis; carbocycles; cascade/tandem/domino reaction; cyclization; cycloaddition; heterocycles; natural fragrances; synthetic odorants; transition-metal catalysis; unsaturated hydrocarbons.

Figure 1

Examples of fragrances with diverse carbocyclic or heterocyclic scaffolds.

Scheme 1

Synthesis of carbocyclic fragrances via the Diels–Alder reaction. (a) Synthesis of Ambrelux and its conversion via acid-promoted annulative rearrangement; (b) total synthesis of georgyone and arborone, with the enantioselective Diels–Alder reaction as a key step.

Scheme 2

Synthesis of fragrant 1,4-cyclohexadiene carboxylates via Co-catalyzed [4 + 2] cyclization.

Scheme 3

Fragrance synthesis by the List group. (a) Synthesis of hydropyran fragrances via the asymmetric hetero-Diels–Alder reaction, catalyzed by imidodiphosphorimidate (IDPi). (b) Total synthesis of the principal ingredient of vetiver oil with IDPi-catalyzed asymmetric Mukaiyama–Michael addition and Co₂(CO)₈-mediated Pauson–Khand [2 + 2 + 1] cyclization as the key steps.

Scheme 4

Synthesis of Si-heterocyclic fragrances via alkyne annulation. (a) Synthesis of sila-analogs of galaxolide with Co-catalyzed [2 + 2 + 2] alkyne cycloaddition as the key step; (b) synthesis of fragrant six-membered silacycles via the Pd-catalyzed [4 + 2] reaction of silacyclobutanes and alkynes.

Scheme 5

Synthesis of fragrant natural products using carbene-involved cyclization. (a) Total synthesis of olibanic acids via semi-hydrogenation and cyclopropanation; (b) total synthesis of carotol via [4 + 1] cyclization and ring-closing metathesis.

Scheme 6

Application of olefin RCM for fragrance chemistry. (a) Synthesis of macrocyclic civetone analogs containing two CF₂ groups; (b) synthesis of a Si-heterocyclic fragrance via hydroformylation and olefin metathesis.

Scheme 7

Synthesis of macrocyclic fragrances via RCM. (a) Total synthesis of (R,Z)-5-muscenone via coupling, alkyne RCM and semi-hydrogenation. (b) Collective synthesis of (+)-muscopyridine and (−)-muscone, using olefin–lactone RCM as the key step. DMP: Dess–Martin periodinane.

Scheme 8

Synthesis of macrocyclic fragrances via rearrangement. (a) Synthesis of a muscone via a successive ring-expansion strategy; (b) Synthesis of diverse macrocyclic ketones via an intramolecular coupling–rearrangement cascade.

Scheme 9

Total synthesis of (−)-β-santalol via asymmetric Diels–Alder reaction and Cu-catalyzed rearrangement of enynol.

Scheme 10

Double bond isomerization for the generation of fragrances. (a) UV-induced alkene isomerization of o-hydroxy cinnamates to release coumarin and fragrant alcohols; (b) asymmetric synthesis of β-bisabolene via Co-catalyzed desymmetric isomerization.

Scheme 11

Synthesis of heterocyclic fragrances via intramolecular hydroalkoxylation. (a) Synthesis of the silicon-containing and ring-expanded analogs of rhubafuran. (b) Synthesis of (−)-elemoxide from (−)-elemol. m-CPBA: m-chloroperbenzoic acid.

Scheme 12

Synthesis of bridged O-heterocyclic fragrances involving carbocation intermediates. (a) Bi-catalyzed cyclization of campholenal-derived enol ethers. (b) Heteropoly acid-catalyzed cyclization of crotonaldehyde with limonene or pinene.

Scheme 13

Synthesis of O-heterocyclic fragrances via an enantioselective Prins reaction catalyzed by imino-imidodiphosphate (iIDP).

Scheme 14

Synthesis of multisubstituted furans or thiophenes via the addition of unsaturated bonds. (a) Synthesis of rosefuran via Pd-catalyzed reaction. (b) The key cyclization step for synthesis of kahweofuran; NMO: N-methylmorpholine oxide. (c) Synthesis of fragrant thiophene derivatives, using C–H functionalization as a key step.

Scheme 15

Total synthesis of 9-epi-Ambrox initiated with a cascade cyclization of dienyne.

Scheme 16

Synthesis of bicyclic musks via the cascade pericyclic reaction of the multifunctional enyne substrates.

Scheme 17

Synthesis of Cashmeran analogs via the oxovanadium-catalyzed cascade cyclization of hydroxy enynes.

Scheme 18

Synthesis of bicyclic fragrances from oxygen-tethered enynes via gold-catalyzed cycloisomerization.